The present invention relates to novel vitamin D derivatives with high binding ability to vitamin D receptors and weak hypercalcemic activity, useful compounds as pharmaceutical agents such as antitumor agents, antirheumatic agents, etc., and novel synthetic intermediates which are useful for synthesis of said compounds.
Activated vitamins D3 including 1xcex1, 25-dihydroxy-vitamin D3 are known to have many physiological activities such as calcium catabolism regulation, growth inhibition and differentiation induction of tumor cells, immunoregulation. However, some activated vitamins D3 disadvantageously cause hypercalcemia during long-term and continuous administration so that they are not suitable for use as antitumor agents, antirheumatic agents or the like. Thus, a number of vitamin D derivatives have been synthesized and examined for the purpose of separating activities of these vitamins D.
For example, JPA No. 267550/86 discloses 1xcex1, 3xcex2-dihydroxy-20(S)-(3-hydroxy-3-methylbutyloxy)-9,10-secopregna-5,7,10(19)-triene and JPA No. 330714/95 discloses a vitamin D derivative substituted by a sulfur atom at the 22-position.
Various vitamin D derivatives having a double bond at the 16-position are described in JPA No. 9861/90, JPA No. 17019/91, JPA No. 188159/95, JPA No. 40975/94, JPA No. 179418/95, U.S. Pat. No. 5087619 and U.S. Pat. No. 5145846, etc. However, none of these compounds are said to have weak hypercalcemic activity.
Many of these known vitamin D compounds have high binding ability to vitamin D receptors but strong hypercalcemic activity, or weak hypercalcemic activity but unsatisfactory binding ability to vitamin D receptors. Therefore, it would be desirable to develop promising compounds with high binding ability to vitamin D receptors and weak hypercalcemic activity.
As a result of careful studies of compounds with high binding ability to vitamin D receptors and weak hypercalcemic activity in view of the above problems, we found that compounds of general formula (1): 
wherein X represents an oxygen or sulfur atom, R11 represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted by a hydroxyl group or a protected hydroxyl group, or a xe2x80x94COR12 group where R12 represents an alkyl, aryl or alkoxy group, R2 represents xe2x80x94OR9 or a hydrogen atom, and R9 and R10 may be the same or different and each represent a hydrogen atom or a protecting group, have high binding ability to vitamin D receptors and weak hypercalcemic activity, and thus accomplished the present invention.
According to one aspect of the present invention, vitamin D derivatives of general formula (1): 
wherein X represents an oxygen or sulfur atom, R11 represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted by a hydroxyl group or a protected hydroxyl group, or a xe2x80x94COR12 group where R12 represents an alkyl, aryl or alkoxy group, R2 represents xe2x80x94OR9 or a hydrogen atom, and R9 and R10 may be the same or different and each represent a hydrogen atom or a protecting group are provided.
In general formula (1), R2 is preferably xe2x80x94OR9.
In general formula (1), R11 is preferably a saturated C1-C15 aliphatic hydrocarbon group which may be substituted by a hydroxyl group.
In general formula (1), R11 is preferably an unsaturated C2-C15 aliphatic hydrocarbon group which may be substituted by a hydroxyl group.
In general formula (1), R11 is preferably a group (2): 
wherein R3 and R4 may be the same or different and each represent a hydrogen atom or a hydroxyl group, or are combined to represent xe2x95x90O, provided that R3 and R4 can not be a hydroxyl groups simultaneously, R5 and R6 each represent a hydrogen atom or a hydroxyl group, but R6 can not be a hydroxyl group simultaneously with R3 or R4, m represents an integer of 1 to 4, and n represents an integer of 0 to 2; or a group (3): 
wherein R5 and R6 may be the same or different and each represent a hydrogen atom or a hydroxyl group, R7 and R8 each represent a hydrogen atom or are combined to represent a covalent bond, p represents an integer of 1 to 3, and q represents an integer of 0 to 2.
In general formula (1), R11 is especially preferably a 3-hyroxy-3-methylbutyl group.
In an embodiment of compounds represented by general formula (1), the 20-position is in S-configuration.
In another embodiment of compounds represented by general formula (1), the 20-position is in R-configuration.
Specific examples of compounds represented by general formula (1) include 1,3-dihydroxy-20-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19), 16-tetraene. Sterically defined examples of this compound include 1xcex1, 30xcex2-dihydroxy-20(S)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene and 1xcex1, 3xcex2-dihydroxy-20(R)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10 (19),16-tetraene.
Other specific examples of compounds represented by general formula (1) include 1xcex1,3xcex2-dihydroxy-20(R)-((E)-4-hydroxy-4-methyl-2-pentenylthio)-9,10-secopregna-5,7,10 (19),16-tetraene and 1xcex1,3xcex2-dihydroxy-20(R)-((E)-4-ethyl-4-hydroxy-2-hexenylthio)-9,10-secopregna-5,7,10(19),16-tetraene.
Other specific examples of compounds represented by general formula (1) include 1xcex1,3xcex2-dihydroxy-20(S)-(2-hydroxy-2-methylpropylthio)-9,10-secopregna-5,7,10(19), 16-tetraene; 1xcex1,3xcex2-dihydroxy-20(R)-(2-hydroxy-2-methylpropyl-thio)-9,10-secopregna-5,7,10(19),16-tetraene; 1xcex1,3xcex2-dihydroxy-20(S)-{2(S)-hydroxy-3-methylbutyloxy}-9,10-secopregna-5,7,10(19),16-tetraene; 1xcex1,3xcex2-dihydroxy-20(S)-{2(R)-hydroxy-3-methylbutyloxy}-9, 10-secopregna-5,7,10(19),16-tetraene; 1xcex1,3xcex2-dihydroxy-20(S)-(2-ethyl-2-hydroxybutylthio)-9,10-secopregna-5,7,10(19),16-tetraene; and 1xcex1,3xcex2-dihydroxy-20(R)-(2-ethyl-2-hydroxybutylthio)-9, 10-secopregna-5,7,10(19),16-tetraene.
According to another aspect of the present invention, compounds of general formula (4): 
wherein X represents an oxygen or sulfur atom, R11 represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted by a hydroxyl group or a protected hydroxyl group, or a xe2x80x94COR12 group where R12 represents an alkyl, aryl or alkoxy group, and R9 and R10 may be the same or different and each represent a hydrogen atom or a protecting group are provided.
In general formula (4), R11 is preferably a saturated C1-C15 aliphatic hydrocarbon group which may be substituted by a hydroxyl group.
In general formula (4), R11 is preferably an unsaturated C2-C15 aliphatic hydrocarbon group which may be substituted by a hydroxyl group.
In general formula (4), R11 is preferably a group (2): 
wherein R3 and R4 may be the same or different and each represent a hydrogen atom or a hydroxyl group, or are combined to represent xe2x95x90O, provided that R3 and R4 can not be a hydroxyl group simultaneously, R5 and R6 each represent a hydrogen atom or a hydroxyl group, but R6 can not be a hydroxyl group simultaneously with R3 or R4, m represents an integer of 1 to 4, and n represents an integer of 0 to 2; or a group (3): 
wherein R5 and R6 may be the same or different and each represent a hydrogen atom or a hydroxyl group, R7 and R8 each represent a hydrogen atom or are combined to represent a covalent bond, p represents an integer of 1 to 3, and q represents an integer of 0 to 2.
In general formula (4), R11 is especially preferably a 3-hyroxy-3-methylbutyl group.
According to another aspect of the present invention, compounds of general formula (24): 
wherein R9 and R10 may be the same or different and each represent a hydrogen atom or a protecting group are provided.
According to still another aspect of the present invention, compounds of general formula (5): 
wherein R9 and R11 may be the same or different and each represent a hydrogen atom or a protecting group, and the conjugated double bond in the formula may be protected by a protecting group are provided.
According to still another aspect of the present invention, compounds of general formula (6): 
wherein R9 and R11 may be the same or different and each represent a hydrogen atom or a protecting group are provided.
According to still another aspect of the present invention, compounds of general formula (7): 
wherein R9 and R10 may be the same or different and each represent a hydrogen atom or a protecting group are provided.
According to still another aspect of the present invention, a process for preparing a vitamin D derivative of general formula (1): 
wherein X represents an oxygen or sulfur atom, R11 represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted by a hydroxyl group or a protected hydroxyl group, or a xe2x80x94COR12 group where R12 represents an alkyl, aryl or alkoxy group, R2 represents xe2x80x94OR9 or a hydrogen atom, and R9 and R10 may be the same or different and each represent a hydrogen atom or a hydroxyl group is provided, which process comprises subjecting a compound of general formula (4a): 
wherein X represents an oxygen or sulfur atom, R1 represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted by a hydroxyl group or a protected hydroxyl group, or a xe2x80x94COR2 group where R12 represents an alkyl, aryl or alkoxy group, and R9 and R10 may be the same or different and each represent a hydrogen atom or a protecting group, to photoreaction, thermal isomerization and deprotection.
According to still another aspect of the present invention, pharmaceutical agents comprising a vitamin D derivative of general formula (1) are provided.